DESCRIPTION: The nucleoside adenosine inhibits significant physiological activity through interaction with specific cell surface receptors. Usually considered a local hormone, the effects of adenosine include vasodilation in the cardiovascular system and depression or neuronal activity in the CNS. Ligands selective for particular subtypes of adenosine receptor have pharmacological significance, not only as biochemical tools to delineate the roles of different receptors in diverse tissues, but also potentially in the clinic. In particular, antagonists specific for the A3 receptor are sought as potential anti-asthmatic, anti- ischemic and anti-inflammatory agents. The natural alkaloid theophylline is an adenosine receptor antagonist. Modification of its substituents has led to other xanthines which are more potent, and selective for A1 or A2 receptors. To date no xanthine has been discovered to show significant antagonist properties at A3 receptors. We have designed and proposed to synthesize 3-aminoxanthines which may be selective A3 receptor antagonists and therefore by useful tools in pharmacology and medicine. They will also allow further refinement of the current models of the interaction of ligands with adenosine receptors. Design of the compounds to be prepared is based on structural comparisons between previously identified selective agonists (adenosines), antagonists (xanthines), and recently identified partial agonist (xanthine nucleosides). Methods for the synthesis of the desired target molecules have been demonstrated by preparation of a very limited subset of 3-aminoxanthines and their nucleosides. These methods will be uses in a systematic way to prepare several series of 3- aminoxanthines so that structure-activity relationships at the various adenosine receptor subtypes ,au be determined. Pharmacological evaluations will be performed at NIDDK as part of an ongoing adenosine receptor ligand screening program.